It is well established that rotaviruses are the leading cause of severe diarrhea among infants and young children. It is estimated that globally 0.6 million children under the age of 5 die annually due to rotavirus diarrhea and another 2 million are hospitalized. 90% of these deaths occur in developing countries. Rotavirus is highly contagious and resistant and, regardless of water quality and available sanitation nearly every child in the world is at risk of infection. A rotavirus vaccine is usually administered to children to protect them from rotavirus infection.
On Jun. 5, 2009, the World Health Organization (WHO) recommended that rotavirus vaccine be included in all national immunization programs. The Rotavirus Vaccine Program and the Accelerated Vaccine Introduction Initiative have worked to study rotavirus vaccines among developing-country populations to assist developing countries in introducing rotavirus vaccines into routine immunization programs. These partnerships are spearheaded by international non-governmental organization PATH, WHO, the U.S. Centres for Disease Control and Prevention, and the Global Alliance for Vaccines and Immunization. International research data suggests that current rotavirus vaccines have 85% to 95% efficacy against severe rotavirus gastroenteritis (RVGE). However, there are concerns while using the same in developing countries where most rotavirus caused deaths occurs, and where access to treatment is limited. One of the main reasons is that immunization schedule for children are neither prepared nor strictly followed in these countries, in spite of the fact that nearly every child in the world will suffer a rotavirus infection before age five. The primary reasons for this are centred on programmatic suitability as well as cost of current vaccines. Programmatic suitability is a new process developed by the WHO for prequalification of vaccines. The prequalification process includes a review of the production process and quality control procedures, review of clinical data, testing of consistency of lots, and a joint WHO and national regulatory authority site visit to the manufacturing facilities. Once the evaluation is complete and if the vaccine is found to be acceptable, in principle, for purchase, it is considered prequalified and is posted on the WHO website.
The existing vaccines are stable only for a limited duration at a particular temperature. It is well known in the art that the vaccine must be stored and transported at refrigeration temperatures maintained at 2° C. to 8° C. Further, it is also well known that vaccines must be administered immediately on being removed from refrigeration. The currently approved vaccine is stable for up to 24 to 36 months at 2° C. to 8° C.
Studies indicate that if one of the presently WHO approved rotavirus vaccine, Rotateq, is inadvertently exposed or stored at temperatures above 8° C., the potency is maintained for the maximum exposure of 48 hours at 9° C. to 25° C. or for a bare 12 hours at 26° C. to 30° C. Indeed if this vaccine is exposed to temperatures above 30° C., or if the time mentioned above has lapsed, the vaccine has to be discarded since it has lost its potency. There is limited data to suggest that if the vaccine is inadvertently exposed to temperatures below 0° C., the potency of the vaccine is maintained.
This necessitates the rotavirus vaccine's strict cold chain storage and transport which is problematic particularly in the developing and low income regions where cold chain required for maintaining vaccine potency and efficacy is imperfect, overburdened or nonexistent, resulting in large amount of vaccine being wasted and in worst case scenario endangering the lives of potential recipients. Reportedly the wastage is as high as 25% to 50%
International patent application number WO2009042202 discloses formulations for preservation of rotavirus. This invention provides formulations and methods for stabilizing viruses in liquid and dried formulations. In particular, formulations are provided including Zn2+ cations that stabilize the viability of Rotaviruses. Methods of vaccination include neutralization of gastric contents and administration of the vaccine formulations of the invention.
US patent application number US 20120308526 discloses sonic low pressure spray drying method. This invention provides methods of spray drying pharmaceutical powders from a vibrating nozzle at low pressures. The method can effectively spray dry thick or viscous solutions or suspensions to provide small uniform particles. The invention includes dry particle compositions prepared by methods of low pressure spraying from vibrating nozzles.
In addition to being thermostable, it is also important that vaccine is suitable from programmatic point of view. The vaccine should be easily prepared in its final form, occupy low volume in cold chain and be easy to dispose after use. Most existing solid form of vaccines including freeze dried vaccines as well as spray dried candidate vaccines are packaged in separate containers/components and require syringe and a vial as well as other complex and costly mechanisms for reconstitution and administration. This creates difficulty in the administration of vaccine and also greatly increases the footprint of the vaccine overburdening the cold chain. This also in turn increases the shipping and distribution challenges, logistics for storage and is prone to potentially fatal reconstitution errors like buffer/vaccine mismatch, contamination, administration of wrong volumes or administration by wrong route, etc.
It is clear that primary packaging has greatest influence on above mentioned programmatic aspects. Number of delivery devices are being developed and tested for vaccine administration. In order for successful mating of these diverse and promising delivery device with the vaccine it is crucial that vaccine formulation be designed that offers greatest flexibility of packaging. Commonly used vial lyophilisation method of stabilization generates vaccine cake that offer least amount of flexibility of packaging in drug delivery devices. Even if lyophilisation process is conducted in drug delivery devices such as dual chamber syringes or cartridges devices the cost due to device as well as processing cost be extremely high. For a vaccine to be broadly adopted in low income regions it is crucial to keep the cost of processing and packaging a vaccine low.
Another component that has influence on price of vaccine is stabilizers and excipients that are used in formulation. It is also crucial from the regulatory and safety point of view that excipient's and stabilizers used should contain neither substances of animal origin nor contain animal component. Indeed in some countries, it is not desirable for cultural and religious reasons as well.
Therefore, to cater to the abovementioned problems there is a need of a thermostable, cost-effective vaccine which will be a great advantage to the vaccination program in solving the logistics of delivering vaccines that retain their potency at room temperature and that which can be afforded by the low income and developing world countries.